ABSTRACT The suppression of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy (ART). Major advances have been made towards this end with the advent of ART regimens. However, despite the sustained suppression of plasma viremia below detectable limits in infected patients for many years on ART regimens, replication competent virus can still be recovered from a variety of sites within the host, and most notably from long-lived quiescent memory CD4+ T lymphocytes. This viral reservoir represents the final impediment to the eradication and clearance of HIV infection or to a sustained virologic remission in the absence of ART. Currently, our understanding of HIV reservoirs in ART recipients is incomplete. Data assessing the impact of early ART initiation during acute infection on reservoir size are limited, especially in the tissues, as are virologic and immunologic surrogates of remission or control of HIV-1. Recent data from my laboratory has shown that persistent viral reservoirs are established very early in SIV infection [1]. However, very early ART can limit the seeding and expansion of cellular reservoirs of HIV [2-4]. Moreover, ART initiated in the earliest stages could significantly limit the size, location and genetic diversity of the HIV-1 reservoir, thereby improving the chance of a virologic remission. The efficacy of potent latency reversal agents (LRAs) or other immunotherapy delivered to very these early ART-treated reservoirs is unclear. Thus, detailed mechanistic studies are needed to define the impact of early ART on virological and immunologic outcomes that are relevant to achieving HIV remission and durable virus control after the cessation of ART [5]. Such investigations are detailed in this proposal. To investigate these hypotheses, we propose the following Specific Aims: 1. Determine the impact of early ART on the nature and distribution of the SIV reservoir during early viral establishment. 2. Assess SIV distribution and clonal expansion during ART initiation and after ART cessation. 3. Determine the impact of combination immunotherapy (TLR7 agonist and PD-L1) on the stability of the viral reservoir after ART cessation.